Drug delivery systems, especially those intended for intravaginal use are known in the art.
U.S. Pat. No. 3,995,633 and U.S. Pat. No. 3,995,634 describe separate, preferably spherical or cylindrical, reservoirs containing different active substances, which are assembled in specially constructed holders.
U.S. Pat. No. 4,237,885 describes a tube or coil of polymeric material which is divided into portions by means of a plurality of “spacers” provided in the tube, after which each of the separate tube portions is filled with a different active substance in a silicone fluid and the two ends of the tube are subsequently connected to one another. In this release system, however, transport (diffusion) of active material from one reservoir to the other takes place through the wall of the tube, especially upon prolonged storage, so that the pre-set fixed release ratio between the active substances in question will change over a period of time.
EP-A-0050867 discloses a two-layered vaginal ring which comprises a pharmacologically acceptable supporting ring covered by two layers preferably of silicone elastomers whereby the inner layer is a silicone elastomer loaded with an active substance.
A ring-shaped silicone vaginal delivery system has been described in U.S. Pat. No. 4,292,965. The use of silicone elastomers is nowadays considered to be less safe and is clearly no longer the material of choice.
U.S. Pat. No. 4,596,576 describes a two-compartment vaginal ring wherein each compartment contains a different active substance. To achieve a suitable ring with a constant release ratio between the various active substances, the end portions of the compartments are joined by glass stoppers.
Drug delivery systems for intravaginal use, and in particular vaginal rings, prepared of polyethylene vinylacetate (EVA) copolymers are also known in the art.
For example, J. A. H. van Laarhoven et al., International Journal of Pharmaceutics 232 (2002) pages 163-173, describes the use of EVA copolymers for the preparation of a vaginal ring.
WO-A-97/02015 describes a two-compartment device: a first compartment consisting of an EVA copolymer core, an EVA copolymer etonogestrel-loaded middle layer and an EVA copolymer non-medicated outer layer; and a second compartment consisting of an EVA copolymer core, loaded with both etonogestrel and ethinyl estradiol, and an EVA copolymer non-medicated outer layer. The preparation of the two-compartments device requires the cutting of fibres in the required lengths and the assembly of the pieces to a ring-shaped device.
EP-A-876815 describes a one-compartment vaginal ring comprising an EVA copolymer core comprising ethinyl estradiol and etonogestrel; and a non-medicated EVA copolymer skin. The progestogenic steroid etonogestrel is dissolved in the EVA copolymer core material in a concentration above the saturation level.
Among the above disclosures, EP-A-876815 clearly sets a standard; it involves a one-compartment design, it obviates the need for silastic polymer by using EVA combinations, and it releases two or more active substances in a substantially constant ratio to one another over a prolonged period in time.
Although the vaginal ring described in EP-A-876815 fulfills its purpose and provides contraception, the design can still be improved upon. The drug delivery device disclosed in EP-A-876815 is physically stable only when stored below room temperature. It requires storage and transport below room temperature, which is expensive and requires a lot of attention. As indicated in EP-A-876815 the progestogen may eventually crystallize out on the exterior surface of the vaginal ring. Such a crystallization of progestogen onto the skin of the device may lead to uncontrolled and high burst release.
It is therefore desirable to avoid the possibility of crystallization of the progestogen on the exterior surface of the vaginal ring when it is stored on or above room temperature (i.e. about 25° C.). At the same time, however, the amounts of progestogen released and release rate should remain unchanged, to ensure a sufficient pharmaceutical effect for use in contraception and/or Hormone Replacement Therapy (HRT).
An improved drug delivery device, easy to prepare, whilst avoiding the possibility of exterior crystallization of the progestogenic compound and still providing sufficient amounts and rates of release of the progestogenic compound for use in contraception and/or HRT has now been found.